Vitamin A and most derivatives thereof having vitamin A activity are water-insoluble, being hydrophobic, lipid-soluble compounds. For example, neither retinoic acid nor retinol are water-soluble. It is known, however, that the glucuronide and glucose derivatives of retinoic acid and retinol are water-soluble. [See, for example, Lippel and Olson, J. Lipid. Res. 9:580-586 (1968); Takabayashi, et al., Chem. Abs. 73:69834z (1970); Barua, et al., Amer J. Clin. Nutr., 43:481-485 (1986).] Water-soluble glycoside derivatives of vitamin A are described in U.S. Pat. No. 4,457,918. The retinoic acid glucuronide and retinol glucuronide have been tested for effects in vitro on cultures of HL-60 cells (a continuous human myeloid cell line): Zile, et al., Proc. Nat. Acad. Sci. USA, 84:2208-2212 1987); and Gallup, et al., First Mid-America Molecular Biol. Colloquium, p. 36, Oct. 1986; and Zile Biol. & Med., 186:269-274 (1987). Under the conditions of the HL-60 system assay, activity similar to retinoic acid and retinol was reported. Both Gallup, et al. and Zile, et al. found that retinoyl .beta.-D-glucuronide (retinoic acid glucuronide) was at least 6-fold less cytotoxic to HL-60 cells than all-trans retinoic acid.
The all-trans form of retinoic acid has been named tretinoin. Cream, gel and liquid preparations containing tretinoin have been approved in the United States for treatment of acne. These preparations are being marketed under the trademark "Retin-A" by the Dermatological Division of Ortho Pharmaceutical Corporation, Raritan, N.J. Presently available strengths of "Retin-A" on a weight percent basis are 0.025% or 0.01% for the gel, 0.1% or 0.05% for the cream, and 0.05% for the liquid. Other potential uses for topical tretinoin have been reported, including treatment of aging skin (Weiss, et al., J. Amer. Acad. Dermat. 19:169-175, 1988), and treatment of xerophthalmia and corneal epithelial wounds (Ubels, et al., Current Eve Research, 4:1049-1057 1985).
Topical tretinoin is being experimentally tested for treatment of aging skin. It has been found, however, that the patients under treatment may experience local erythema and peeling of the skin, as has been observed in acne treatment. The degree of irritation varies with the strength of the preparation and the frequency of its application, higher concentrations and more frequent application producing a greater number of skin irritation side effects. When such side effects are noted, the treatment can be discontinued for a number of days, a preparation of lower strength used, or the time between applications can be increased. In view of the clinically beneficial results obtained in the treatment of acne and the promising results with respect to improving the condition of aging skin, it would be desirable to utilize a less irritating form of retinoic acid.
Weiss, et al. (1988), cited above, reported a double-blind study confirming earlier published reports that treatment with tretinoin is capable of at least partly reversing structural damage associated with extrinsic aging (photoaging) of the skin. I order to minimize skin irritation, Weiss et al. started treatment with 0.1% tretinoin cream on a daily basis, and then advanced the patients to twice-a-day applications. When a patient was unable to tolerate the 0.1% cream, the patient was switched to a 0.05% cream. Most patients were able to continue with the treatments. However, during the course of their study Weiss, et al. found that "more than 90% of the patients experienced some degree of dermatitis in the tretinoin treated areas" (page 172, col. 1). The areas of the skin found most susceptible to retinoid dermatitis were the sides of the neck, the V-area of the neck and chest, the ventral arms, and the antecubital fossae.